Tapentadol of formula Ia, marketed as its hydrochloride salt under the trade name

Nucynta, is a centrally-acting analgesic and is chemically known as 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol.
It has a unique dual mode of action as an agonist at the g-opioid receptor and as a norepinephrine reuptake inhibitor. μ-Opioid agonists are drugs that bind to and activate μ-opioid receptors in the central nervous system. These drugs modify sensory and affective aspects of pain, inhibit the transmission of pain at the spinal cord and affect activity parts of the brain that control how pain is perceived. Norepinephrine reuptake inhibitors are a type of central nervous system medication that increases the level of norepinephrine in the brain by inhibiting its re-absorption into nerve cells; these compounds have analgesic properties.
Tapentadol and its analogues are first disclosed in U.S. Pat. No. RE 39,593 (reissue of U.S. Pat. No. 6,248,737). According to the process disclosed in above patent, tapentadol, is prepared by process as shown in the following scheme:

Tapentadol is prepared by starting from 3-bromoanisole and 1-dimethylamino-2-methylpentan-3-one. 3-Bromoanisole is reacted with 1-dimethylamino-2-methylpentan-3-one to form racemic tertiary alcohol intermediate, which is then resolved by chiral HPLC. The resolved intermediate is then converted into corresponding chloride compound, followed by reduction with zinc borohydride, zinc cyanoborohydride or tin cyanoborohydride and then finally converted into tapentadol by demethylation using hydrobromic acid. The process involves formation of hydrochloride salts of intermediates which are then used in the next stage. Hydrochloride formation of intermediates is carried out in the presence of trimethylchlorosilane, which is a highly flammable liquid and being hazardous, hence not advisable to use in the industrial scale. The other disadvantage of the above process is resolution by the chiral HPLC, which is not amenable for industrial level synthesis.
U.S. Pat. No. 7,417,170 discloses a process for the preparation of racemic 3-(3-methoxyphenyl)-N,N,2-trimethylpentanamine, an intermediate of tapentado,1 by the reaction of (2S,3S)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-3-pentanol with an acid to form a mixture of cis and trans isomer of alkene intermediate, the resulting mixture is then hydrogenated to form a mixture of (2R,3R) and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamine as outlined below.

US patent publication 2006/0167318 discloses a process for the preparation of racemic 3-(3-methoxyphenyl)-N,N,2-trimethylpentanamine, an intermediate of tapentadol, by dehydrating corresponding (2S,3S) tertiary alcohol intermediate, followed by reduction of resulting alkene intermediate using heterogeneous catalyst to form a mixture of (2R,3R) and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamine as outlined below.

PCT publication WO 2008/012283 discloses a process for the preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamine, an intermediate of tapentadol, by treating corresponding hydroxy compound with acid chloride, ethyl oxalyl chloride or trifluoro acetic acid anhydride, then converted to (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamine or its acid addition salts as outlined below.

In view of the above, there is an urgent need to develop a cost effective and industrially advantageous process for the synthesis of 1-phenyl-3-dimethylaminopropane derivatives. Thus, present invention fulfills the need in the art and provides an industrially advantageous process for preparing 1-phenyl-3-dimethylaminopropane derivatives, in particular tapentadol and its pharmaceutically acceptable salts thereof that does not involve chiral chromatographic technique for separation of isomers.